Specific role of dopamine D1 receptors in spinal network activation and rhythmic movement induction in vertebrates

Abstract

Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain functions. DA was also found in in vitro isolated invertebrate preparations to activate per se the central pattern generator for locomotion. However, it is less clear whether such a role as an activator of central neural circuitries exists in vertebrate species. Here, we studied in vivo the effects induced by selective DA receptor agonists and antagonists on hindlimb movement generation in mice completely spinal cord-transected (Tx) at the low-thoracic level (Th9/10). Administration of D1/D5 receptor agonists (0.5-2.5 mg kg(-1), i.p.) was found to acutely elicit rhythmic locomotor-like movements (LMs) and non-locomotor movements (NLMs) in untrained and non-sensory stimulated animals. Comparable effects were found in mice lacking the D5 receptor (D5KO) whereas D1/D5 receptor antagonist-pretreated animals (wild-type or D5KO) failed to display D1/D5 agonist-induced LMs. In contrast, administration of broad spectrum or selective D2, D3 or D4 agonists consistently failed to elicit significant hindlimb movements. Overall, the results clearly show in mice the existence of a role for D1 receptors in spinal network activation and corresponding rhythmic movement generation.

Figure 1. Effects of D1-like receptor agonists on hindlimb movement induction in CD1 mice

Video images displaying a typical step cycle on a treadmill (or a 4 s bout of recording when no movement was found) prior to drug administration (A) and 15 min after 1–2 mg kg⁻¹ SKF-81297 (B). Stick diagrams apposed on photographs were derived from three primary joints (i.e. hip, knee and ankle). Significant inductions of locomotor-like movements (LM, E; movements per minute (mov/min)), non-locomotor movements (NLM, D), movement amplitude (F), average combined scores (ACOS, H) and incidence (G) in paraplegic CD1 mice. *P < 0.05 and **P < 0.01 compared with pre-injection.

Figure 2. SKF-81297-induced movements in CD1 and C57BL/6 mice

Significant induction of NLMs (A), LMs (B), amplitude (C) and ACOS (D) following administration of 0.5–2.5 mg kg⁻¹ SKF-81297 in paraplegic CD1 and C57BL/6 Tx mice. *P < 0.05, **P < 0.01 and ***P < 0.001 compared with pre-injection.

Figure 3. SKF-81297-induced movements in D5KO mice

Significant induction of LMs, NLMs, amplitude (A) and ACOS (B) following administration of 0.5–2.5 mg kg⁻¹ SKF-81297 in paraplegic D5KO mice. *P < 0.05, **P < 0.01 and ***P < 0.001 compared with pre-injection. Note that right end ordinate scales are used only for movement amplitude (A) and incidence (B) values.

Figure 4. D1/D5 antagonist pretreated vs non-pretreated animals that received SKF-81297

Significant reductions of NLMs (A), LMs (B), amplitude (C) and ACOS (D) following administration of 0.5–2.5 mg kg⁻¹ SKF-81297 in CD1, C57BL/6 and D5^−/− Tx mice previously pre-treated with 1.0 mg kg⁻¹ SCH23390. *P < 0.05, **P < 0.01 and ***P < 0.001.

Figure 5. D2, D3 and D4 receptor agonist-induced effects

D2-like receptor agonists (i.e. quinpirole – D2/D3 preferred agonist, 7-OH-DPAT – preferred D3 agonist, and PD168077 – preferred D4 agonist) failed to significantly affect NLMs (A), LMs (B), movement amplitude (C), incidence (D) and ACOS (E) in paraplegic animals. *P < 0.05 compared with pre-injection.

Figure 6. Effects of apomorphine on hindlimb movement induction

Apomorphine failed to significantly change LMs, NLMs, amplitude (A) or ACOS and incidence (B). Note that right end ordinate scales are used only for movement amplitude (A) and incidence (B) values.

Figure 7. Group comparisons

Significant inductions of NLMs (A), LMs (B), movement amplitude (C) and ACOS (D) following administration of 0.5–2.5 mg kg⁻¹ D1-like, D2-like or D1/D2-like agonists in Tx animals. ^†P < 0.05, *P < 0.05, **P < 0.01 and ***P < 0.001.